Exosomal lncRNA ROR1-AS1 from cancer-associated fibroblasts inhibits ferroptosis of lung cancer cells through the IGF2BP1/SLC7A11 signal axis.

Targeting ferroptosis is a potential strategy for cancer treatment. Activated cancer-associated fibroblasts (CAFs) can affect the progression of lung cancer through exosomes. This study investigated the mechanism by which exosomal lncRNA ROR1-AS1 derived from CAFs affects ferroptosis of lung cancer cells. CAFs were identified by western blot and immunofluorescence. Exosomes derived from CAFs (CAF-exo) were analyzed by transmission electron microscope, nanoparticle tracking analysis and western blot. The expression levels of ROR1-AS1, IGF2BP1 and SLC7A11 in lung cancer were analyzed by bioinformatics analysis and detected by qPCR and western blot. The lung cancer cells were treated with Erastin and/or CAF-exo, then cell viability was detected by cell counting kit-8, and the ferroptosis-related indicators were detected by corresponding kits. The relationship between IGF2BP1 and ROR1-AS1 or SLC7A11 was determined by RNA pull down and RNA immunoprecipitation, and their effects on cell ferroptosis were confirmed by rescue experiments. Xenotransplantation experiment was used to determine the effect of CAF-exo on tumor growth and ferroptosis in vivo. Immunohistochemistry was used to identify the Ki-67 and 4-HNE expression. ROR1-AS1, IGF2BP1 and SLC7A11 were upregulated in lung cancer and indicated poor prognosis. LncRNA ROR1-AS1 increased the stability of SLC7A11 mRNA by interacting with IGF2BP1. Exosomal ROR1-AS1 from CAFs inhibited ferroptosis of lung cancer cells in vitro and in vivo. The effect of ROR1-AS1 overexpression or IGF2BP1 overexpression on ferroptosis of lung cancer cells was partially reversed by IGF2BP1 silencing or SLC7A11 inhibition. CAFs secrete exosomal ROR1-AS1 to promote the expression of SLC7A11 by interacting with IGF2BP1, thereby inhibiting ferroptosis of lung cancer cells.

Yao F ，Zhao Y ，Wang G ，Zhao M ，Hong X ，Ye Z ，Dong F ，Li W ，Deng Q ... -  《-》

Cancer-associated fibroblasts-derived exosomes promote lung cancer progression by OIP5-AS1/ miR-142-5p/ PD-L1 axis.

Cancer-associated fibroblasts (CAFs) are the most important stromal cells in the tumor microenvironment (TEM) and have been reported to regulate various cancer development. Exosomes are considered important elements involved in intercellular communication and TME regulation, while the potential function of CAFs in lung cancer immunosuppressive microenvironments remains unknown. CAFs-derived exosomes (CAFs-exo) and normal fibroblasts (NFs)-derived exosomes (NFs-exo) were isolated by ultra-centrifugation and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blot analysis. A549 cells were co-cultured with peripheral blood mononuclear cells (PBMCs). Flow cytometry assay was performed to detect the killing role of PBMCs on A549 cells. Bioinformatics and luciferase reporter assays were used to analyze the relationship among microRNA (miRNA), long non-coding RNA (lncRNA) and target gene. BALB/c mice were used to construct the lung cancer model by subcutaneous injection. Programmed death ligand 1 (PD-L1) was up-regulated in lung cancer tissues and cells. PD-L1 also up-regulated in CAFs cell medium-mediated A549 cells. CAFs decreased PBMCs induced-cell apoptosis through increasing PD-L1 in A549 cells. Moreover, CAFs transferred exosomes to lung cancer cells to suppress the killing effect of PBMCs through up-regulating PD-L1. Using microarray assays, opa-interacting protein 5 antisense RNA 1 (OIP5-AS1) level was highly expressed in CAFs-exos. After treatment by CAFs-exos, miR-142-5p level was significantly down-regulated in A549 cells. OIP5-AS1 served as a sponge to target miR-142-5p and negatively regulated miR-142-5p expression in lung cancer cells. In addition, PD-L1 was a direct target of miR-142-5p. CAFs derived exosomal OIP5-AS1 reduced PBMCs induced-cell apoptosis and promoted tumor growth through decreasing miR-142-5p and up-regulating PD-L1. CAFs-derived exosomes suppressed the role of PBMCs induced-killing of lung cancer cells and promoted lung cancer progression by OIP5-AS1/ miR-142-5p/ PD-L1 axis, which provided a potential opportunity for diagnosis and treatment of lung cancer.

Jiang Y ，Wang K ，Lu X ，Wang Y ，Chen J ... -  《-》

Silencing lncRNA SLC16A1-AS1 Induced Ferroptosis in Renal Cell Carcinoma Through miR-143-3p/SLC7A11 Signaling.

Li YZ ，Zhu HC ，Du Y ，Zhao HC ，Wang L ... -  《-》

Exosome-derived circUPF2 enhances resistance to targeted therapy by redeploying ferroptosis sensitivity in hepatocellular carcinoma.

Advanced hepatocellular carcinoma (HCC) can be treated with sorafenib, which is the primary choice for targeted therapy. Nevertheless, the effectiveness of sorafenib is greatly restricted due to resistance. Research has shown that exosomes and circular RNAs play a vital role in the cancer's malignant advancement. However, the significance of exosomal circular RNAs in the development of resistance to sorafenib in HCC remains uncertain. Ultracentrifugation was utilized to isolate exosomes (Exo-SR) from the sorafenib-resistant HCC cells' culture medium. Transcriptome sequencing and differential expression gene analysis were used to identify the targets of Exo-SR action in HCC cells. To identify the targets of Exo-SR action in HCC cells, transcriptome sequencing and analysis of differential expression genes were employed. To evaluate the impact of exosomal circUPF2 on resistance to sorafenib in HCC, experiments involving gain-of-function and loss-of-function were conducted. RNA pull-down assays and mass spectrometry analysis were performed to identify the RNA-binding proteins interacting with circUPF2. RNA immunoprecipitation (RIP), RNA pull-down, electrophoretic mobility shift assay (EMSA), immunofluorescence (IF) -fluorescence in situ hybridization (FISH), and rescue assays were used to validate the interactions among circUPF2, IGF2BP2 and SLC7A11. Finally, a tumor xenograft assay was used to examine the biological functions and underlying mechanisms of Exo-SR and circUPF2 in vivo. A novel exosomal circRNA, circUPF2, was identified and revealed to be significantly enriched in Exo-SR. Exosomes with enriched circUPF2 enhanced sorafenib resistance by promoting SLC7A11 expression and suppressing ferroptosis in HCC cells. Mechanistically, circUPF2 acts as a framework to enhance the creation of the circUPF2-IGF2BP2-SLC7A11 ternary complex contributing to the stabilization of SLC7A11 mRNA. Consequently, exosomal circUPF2 promotes SLC7A11 expression and enhances the function of system Xc- in HCC cells, leading to decreased sensitivity to ferroptosis and resistance to sorafenib. The resistance to sorafenib in HCC is facilitated by the exosomal circUPF2, which promotes the formation of the circUPF2-IGF2BP2-SLC7A11 ternary complex and increases the stability of SLC7A11 mRNA. Focusing on exosomal circUPF2 could potentially be an innovative approach for HCC treatment.

Dong FL ，Xu ZZ ，Wang YQ ，Li T ，Wang X ，Li J ... -  《JOURNAL OF NANOBIOTECHNOLOGY》

Research on the mechanism of exosomes from different sources influencing the progression of lung cancer.

As a key regulator of intercellular communication, exosomes are essential for tumor cells. In our study, we will explore the mechanisms of exosomes from different sources on lung cancer. We isolated CD8+T cells and cancer-associated fibroblasts (CAFs) from venous blood and tumor tissues of lung cancer patients, and isolated exosomes. MiR-2682 was high expression in CD8+T-derived exosomes, and lncRNA-FOXD3-AS1 was upregulated in CAF-derived exosomes. Online bioinformatics database analysis showed that RNA Binding Motif Protein 39 (RBM39) was identified as the target of miR-2682, and eukaryotic translation initiation factors 3B (EIF3B) was identified as the RNA binding protein of FOXD3-AS1. CD8+T-derived exosomes inhibited the growth of A549 cells and promoted apoptosis, while miR-2682 inhibits reversed these effects of CD8+T-derived exosomes. CAF-derived exosomes promoted the growth of A549 cells and inhibited apoptosis, while FOXD3-AS1 siRNA reversed the effect of CAF-derived exosomes. Mechanism studies have found that miR-2682 inhibits the growth of lung cancer cells by inhibiting the expression of RBM39. FOXD3-AS1 promoted the growth of lung cancer cells by binding to EIF3B. In vivo experiments showed that CD8+T cell-derived exosome miR-2682 inhibited lung cancer tumor formation, while CAF-derived exosome FOXD3-AS1 promoted lung cancer tumor formation. This study provides mechanistic insights into the role of miR-2682 and FOXD3-AS1 in lung cancer progression and provides new strategies for lung cancer treatment.

Mao G ，Liu J 《-》